Dietary restriction extends lifespan, improves mid-life vigor, and retards age-related disease in many species. Mechanisms underlying these benefits are not well understood. Defining the cellular pathways by which dietary restriction is initiated and maintained holds potential for combating obesity, diseases of old age such as cancer, and the general functional decline that accompanies aging. We have begun to investigate how microRNAs (miRNAs), small molecules that target partially homologous transcripts to block their translational expression, impact the "quality of aging" (healthspan) in the powerful experimental model C. elegans. In this animal, conserved genes can be readily manipulated to address specific hypotheses regarding their activities. Moreover, nearly all the C. elegans microRNA genes are likely to have been identified, deletions of most of these genes have been recently generated, and our preliminary work suggests several miRNAs impact lifespan and and/or healthspan phenotypes. In mammalian systems, miRNA expression profiles change with different metabolic conditions, although no studies to date have addressed changes in dietary restriction. The working hypothesis we propose to test here is that specific microRNAs exert significant effects on the initiation and/or maintenance of dietary restriction metabolism. If we identify these miRNAs and figure out how they work, we could suggest manipulation of their mammalian counterparts to improve healthy mid- and late-life. We will therefore exploit the considerable experimental advantages of C. elegans models to identify miRNAs that are differentially expressed in dietary restricted animals, and we will genetically test candidates for causative action in DR induction and/or maintenance. Because dietary restriction appears to transpire by a fundamental mechanism conserved from nematodes to humans and because virtually nothing is known yet of microRNA modulation of dietary restriction, our planned work should produce data relevant to human biology that pioneers a new area in dietary restriction research with implications for therapeutic development. PUBLIC HEALTH RELEVANCE: Dietary restriction, a regimen of reduced caloric intake, extends lifespan, limits the onset of age-associated diseases (for example, cancer) and reduces the rate of age-related decline across species. Finding molecular strategies to induce dietary restriction metabolism could therefore be exploited for wide therapeutic benefit. We propose to identify natural conserved small molecules (microRNAs) that can shift metabolism into health-promoting dietary restriction to limit fat accumulation and obesity, to reduce age-associated disease, and to delay functional declines that accompany normal aging.